title: Human β-defensin 3 induces STAT1 phosphorylation, tyrosine phosphatase activity, and cytokine synthesis in T cells.
abstract: The AMP hBD-3 stimulates numerous immune effector functions in myeloid cells and keratinocytes, predominantly through the MAPK signaling cascade. In contrast, hBD-3 was reported to neutralize the activation of T cells by antagonizing MAPK signaling initiated by SDF-1α through CXCR4. With the use of complementary proteomic and immunochemical approaches, we investigated possible stimulatory effects of hBD-3 on T cells and demonstrate that hBD-3 induces STAT1 tyrosine phosphorylation within 5 min yet is unable to induce MAPK activation. Inclusion of a PTPase inhibitor increased hBD-3-induced phosphorylation dramatically, suggesting that hBD-3 also stimulates PTPase activity concurrently. The increase in PTPase activity was confirmed by demonstrating that hBD-3 suppresses IFN-γ-induced STAT1 tyrosine phosphorylation but not STAT1 serine and ERK1/2 threonine phosphorylation and stimulates the translocation of SHP-2 into the nucleus within 15 min. The signaling pathways initiated by hBD-3 may lead to the observed enhancement of distinct T cell effector functions during TCR activation, such as the increase in IL-2 and IL-10, but not IFN-γ secretion. Thus, hBD-3 initiates distinct lineage-specific signaling cascades in various cells involved in host defense and induces a concurrent tyrosine kinase and tyrosine phosphatase signaling cascade that may activate simultaneously the targeted T cells and inhibit their response to other immune mediators. Furthermore, these results suggest that this evolutionarily conserved peptide, which exhibits a broad spectrum of antimicrobial and immunomodulatory activities, serves to integrate innate and adaptive immunity.
authors.affiliation: Department of Medicine, Case Western Reserve University School ofMedicine, Cleveland, Ohio 44106-4952, USA.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Meisch
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Vogel
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Schlatzer
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Li
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.forename: Alan D
authors.initials: AD
authors.lastname: Levine
mesh_terms: D021581:Active Transport, Cell Nucleus; D018106:CD28 Antigens / Q000502:physiology; D002460:Cell Line; D002853:Chromatography, Liquid; D016207:Cytokines / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D053612:Janus Kinases / Q000502:physiology; D020935:MAP Kinase Signaling System; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D053719:Tandem Mass Spectrometry; D023083:beta-Defensins / Q000494:pharmacology*
chemical_list: D018106:CD28 Antigens; D016207:Cytokines; C422950:DEFB103A protein, human; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D023083:beta-Defensins; D007371:Interferon-gamma; D053612:Janus Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases
keywords: IFN-γ; IL-10; IL-2; T lymphocyte; antimicrobial peptides; signal transduction